Objective: Studies have demonstrated the utility of closed-loop neuromodulation in treating focal onset seizures. There is an utmost need of neurostimulation therapy for generalized tonic-clonic seizures. The study goals are to map the thalamocortical network dynamics during the generalized convulsive seizures and identify targets for reliable seizure detection.
Methods: Local field potentials were recorded from bilateral cortex, hippocampi, and centromedian thalami in Sprague-Dawley rats. Pentylenetetrazol was used to induce multiple convulsive seizures. The performances of two automated seizure detection methods (line length and P-operators) as a function of different cortical and subcortical structures were estimated. Multiple linear correlations-Granger's Causality was used to determine the effective connectivity.
Results: Of the 29 generalized tonic-clonic seizures analyzed, line length detected 100% of seizures in all the channels while the P-operator detected only 35% of seizures. The detection latencies were shortest in the thalamus in comparison to the cortex. There was a decrease in amplitude correlation within the thalamocortical network during the seizure, and flow of information was decreased from thalamus to hippocampal-parietal nodes.
Significance: The preclinical study confirms thalamus as a superior target for automated detection of generalized seizures and modulation of synchrony to increase coupling may be a strategy to abate seizures.
RESULTS: A total of 150 hours (15 hours of awake and 15 hours of sleep per subject X 5 subjects) was analyzed. SOZ were- temporo-insular, amygdala-hippocampus, temporo-perisylvian (N= 2) and hippocampal-anterior cingulate. Descriptive analyses included means, standard deviations, medians, and ranges of spikes were in table 1. For the SOZ the mean spike count for awake state were lower than sleep state (70.16 ± 22.36 compared to 97.52 ± 23.45, respectively; (t(df= 785)= -16.46, p0.001). For the TH channels the mean spike count for awake state were lower than sleep state (15.19 ± 11.29 compared to 72.43 ± 39.65, respectively; (t(df= 440.1)= -27.06, p0.001). Control channels did not show a significant difference between SOV. The differences between the channels (SOZ, TH and C) during different SOV were significantly different (Table 1 and Fig1). The ratio of spikes between SOZ:TH during awake and sleep were 4.6 and 1.6 respectively. The morphology of the spikes (duration, amplitude) was compared between SOZ and TH (Fig 1).
CONCLUSIONS:Following transition from awake to sleep, there was a- 1) significant increase in spike count in SOZ and TH; and 2) the increment in TH was significantly higher than in SOZ. Spikes in SOZ were faster than in TH.
FUNDING:This study was funded by the NSF EPSCoR OIA 1632891.
Direct electrical stimulation (DES) of the cortex is a clinically indispensable brain mapping technique that provides reliable information about the distribution of eloquent cortex and its connectivity to the white matter bundles (David et al., 2010). Apart from functional mapping, DES is also an efficient way to map neuroanatomical pathways connected to the stimulated node (Duffau, 2015, Lacruz et al., 2007, Martino et al., 2010, Matsumoto et al., 2007). The stimulated node act as an input gate into the large-scale network whose responses are mapped with high temporospatial precision using electrocorticography (ECoG). Evoked neural responses (called as cortico-cortical evoked potentials-CCEP) are measured as the variation in amplitude and first-peak latency (N1) that helps to estimate patient-specific neuroanatomical pathways in vivo (Duffau, 2015, Keller et al., 2014). Evoked cortical responses below 10 milliseconds (ms) reflect mono- or oligosynaptic connectivity while responses longer than 10 ms may reflect poly-synaptic connectivity (Keller et al., 2014, Logothetis et al., 2010). Unfortunately, most CCEP studies preclude mapping the early short-latencies (<10 ms) as the injected current saturates the amplifier of the clinical EEG acquisition system. Capitalizing on the improved clinical EEG acquisition system (Natus® Quantum®) that allows higher sampling (16 kHz) from 256 channels, we explored mapping short-latency cortical responses (<10 ms) to stimulation of ventral anterior nucleus of the thalamus (VA). Based on the known anatomical connectivity of the VA thalamus (often considered a part of the motor and limbic thalamus) (Aggleton et al., 1980, McFarland and Haber, 2000, Percheron et al., 1996), we hypothesize that short-latency evoked potentials (SLEP: <10 ms) can be mapped in cortices that receive afferents from the VA.
The study was performed on a 22-year old right-handed man with drug-resistant focal epilepsy who underwent stereo EEG (SEEG) exploration for localization of seizures. Post-SEEG, the seizures were localized to the left orbitofrontal region that was resected, and the patient remained seizure-free (>12 months). One of the depth electrodes sampling the frontal-operculum and insula was progressed medially to sample VA. The study was approved by IRB and written informed consent was obtained to record field potentials from the thalamus. Stimulation was performed (Nicolet® stimulator) when all antiseizure medications were discontinued to record seizure. Stimulation parameters were: bipolar stimulation (thalamic deepest contact as a cathode and the adjacent contact as anode), 1 Hz biphasic pulse wave with pulse width 300 µsec, current 3 mA and train of 40 seconds. The post-implant computed tomography (CT) image was co-registered with the pre-implant structural MRI using Advanced Normalization Tools (Avants et al., 2009). We then combined registration strategies in LeadDBS (Horn and Kuhn, 2015) and iElectrodes (Blenkmann et al., 2017) to map the electrode trajectory and the final thalamic target. The cortical regions implanted were confirmed with AAL2 atlas (Rolls et al., 2015), and the thalamic subnuclei were identified using the mean histological thalamic atlas (Krauth et al., 2010)
Background and purpose: Focal seizures can arise from coordinated activity across large-scale epileptic networks and propagate to regions that are not functionally altered but are recruited by epileptiform discharges. In preclinical models of focal epilepsy, the thalamus is recruited by cortical onset seizures, but it remains to be demonstrated in clinical studies. In this pilot study, the authors investigate whether seizures with onset within and outside the mesial temporal structures are detected in the anterior thalamus (ATN).
Methods: After written consent, three subjects with suspected temporal lobe epilepsy undergoing stereotactic electrode implantation were recruited prospectively for thalamocortical depth EEG recordings. Three seizure detection metrics (line length-LL, Laplace operator-Lap; Teager energy-TE) were studied within the seizure onset zone and ATN.
Results: The LL, Lap, and TE metrics detected 40 (95%) seizures each in the ATN before the
behavioral manifestation. Rates of detection in the seizure onset zone were 40 (95%), 42 (100%), and 41 (98%), respectively. The mean detection latency in ATN from SOZ ranged from 0.25- 5.17 secs. Seizures were localized to amygdala-hippocampus, temporal pole, anterior insula and superior temporal gyrus.
Conclusions: The pilot study demonstrates that seizures in mesial temporal and temporal-plus epilepsies (i.e., temporoperisylvian) can be detected reliably in the ATN. Further studies are needed to validate these findings.
The thalamic nuclei play diverse roles in the initiation, propagation, and termination of temporal lobe seizures. The role of the anterior nucleus of the thalamus (ANT) - a node that is integral to the limbic network is unclear. The objective of this study was to characterize temporal and - spectral patterns of ANT ictal recruitment in drug-resistant temporal lobe epilepsy (TLE). We hypothesized that seizures localized to the temporolimbic network are likely to recruit ANT, and the odds of recruitment were higher in seizures that had altered consciousness. Ten patients undergoing stereo-electroencephalography (SEEG) were recruited prospectively to record field potentials from the ANT. Using epileptogenicity index and line length, we computed the number of seizures that recruited the ANT (recruitment ratio), the recruitment latencies between the ANT and the epileptogenic zone (EZ), and latency of ANT recruitment to clinical manifestation for seventy-nine seizures. We observed that seizures localized to mesial temporal subregions (hippocampus, amygdala, anterior cingulate) have a higher predilection for ANT recruitment, and the recruitment was faster (ranged 5-12 secs) and preceded clinical onset for seizures that impaired consciousness. Seizures that recruited ANT lasted significantly longer (t=1.795, p=0.005). Recruitment latency was inversely correlated to seizure duration (r=-0.78, p=0.004). Electrical stimulation of the EZ induced seizures, in which early recruitment of ANT was confirmed. Stimulation of ANT did not induce a seizure. Finally, we tested the hypothesis that spectral and entropy-based features extracted from thalamic field potentials can distinguish its state of ictal recruitment from other interictal states (including awake, sleep). For this, we employed classification machine learning that discriminated thalamic ictal state from other interictal states with high accuracy (92.8%) and precision (93.1%). Among the features, the emergence of the theta rhythm (4-8 Hz) maximally discriminated the endogenous ictal state from other interictal states of vigilance. These results prompt a mechanistic role for the ANT in the early organization and sustaining of seizures, and the possibility to serve as a target for therapeutic closed-loop stimulation in TLE.
The goal of thalamic deep brain stimulation in epilepsy is to engage and modulate the epileptogenic network. We demonstrate how the anterior nucleus of thalamus (ANT) stimulation engages the epileptogenic network using electrophysiological measures (gamma response and post-stimulation excitability).
Five patients with suspected temporal lobe epilepsy syndrome, undergoing stereo-electroencephalography (SEEG), were enrolled in the IRB approved study to undergo recording and stimulation of the ANT. We analyzed the extent of gamma-band response (activation or suppression) and post-stimulation change in excitability in various cortical regions during low (10Hz) and high (50Hz) frequency stimulations.
10Hz stimulation increased cortical gamma, whereas 50Hz stimulation suppressed the gamma responses. The maximum response to stimuli was in the hippocampus. High epileptogenicity regions were more susceptible to stimulation. Both 10-and 50Hz stimulations decreased post-stimulation cortical excitability. The greater the gamma-band activation with 10Hz stimulation, the greater was the decrease in post-stimulation excitability.
Arousal is the most primitive, powerful instinct with survival benefit present in all vertebrates. Even though the arousal systems are classically viewed as “ascending” brainstem phenomena, there is a “descending” cortical feedback system that maintains consciousness. In this study, we provide electrophysiological confirmation that seizures localized to the anterior cingulum can behaviorally manifest as paroxysms of arousal from sleep.
Temporal dynamics of arousal induced by anterior cingulate seizures were analyzed by using multiple modalities including stereoelectroencephalography (phase lag index and phase amplitude coupling), lead-1 ECG (point-process heart rate variability analysis) and diffusion tractography (DTI).
The ictal arousal was associated with an increase in synchronization in the alpha band and an increase in local theta or alpha-gamma phase-amplitude coupling. In comparison to seizures that lacked clinical manifestations, ictal arousal was associated with an increase in heart rate but not heart rate variability. Finally, DTI demonstrated degeneration in white fiber tracts passing between the anterior cingulum and anterior thalamus ipsilateral to the epileptogenic cortex. The patient underwent resection of the anterior cingulum, and histopathology confirmed focal cortical dysplasia type II.
Anterior cingulate seizures inducing behavioral arousal have identifiable autonomic and EEG signatures.
Despite numerous imaging studies highlighting the importance of the thalamus in a patient’s surgical prognosis, human electrophysiological studies involving the limbic thalamic nuclei are limited. The objective of this study was to evaluate the safety and accuracy of robot-assisted stereotactic electrode placement in the limbic thalamic nuclei of patients with suspected temporal lobe epilepsy (TLE).
After providing informed consent, 24 adults with drug-resistant, suspected TLE undergoing evaluation with stereoelectroencephalography (SEEG) were enrolled in the prospective study. The trajectory of one electrode planned for clinical sampling of the operculoinsular cortex was modified to extend it to the thalamus, thereby preventing the need for additional electrode placement for research. The anterior nucleus of the thalamus (ANT) (n = 13) and the medial group of thalamic nuclei (MED) (n = 11), including the mediodorsal and centromedian nuclei, were targeted. The postimplantation CT scan was coregistered to the preoperative MR image, and Morel’s thalamic atlas was used to confirm the accuracy of implantation.
RATIONALE: Recent studies using multi-modality brain-mapping techniques have elaborately elucidated epilepsy as a disease with anomalous network montages. Multiple studies in preclinical models of limbic/mesial Temporal lobe epilepsy (TLE) have indirectly supported the concept that thalamus intimately redefines the behavioral expression of limbic seizures. In a subset of patients with failed anterior temporal lobectomy (ATL), electrophysiological and imaging abnormalities in thalamo-temporal connectivity were significantly associated with failure to achieve adequate control of seizures. Among the different available pre-operative mapping techniques, stereoelectroencephalography (SEEG) allows simultaneous electrophysiological sampling of cortical and subcortical structures in three-dimensions and has been adopted in our Level-IV epilepsy center. Here we report our preliminary experience in the pre-surgical evaluation of cortico-thalamic dynamics using stereo depth EEG in a patient with failed ATL. The purpose of this study was to map the temporal dynamics of thalamic activity during transition from inter-ictal to simple and complex partial ictus states.
RATIONALE: Interictal spikes are brief (< 250 milliseconds), high-amplitude discharges observed in the EEG (scalp and intracranial) in patients who are predisposed to spontaneous seizures. The temporo-spatial distribution of spikes is variable and depends on states of vigilance (SOV) and seizure. In focal epilepsy, spikes are often found in regions beyond the seizure onset zone(SOZ) and are defined as “irritative zone”(IZ). Continuous dynamic interactions between SOZ and IZ are influenced by underlying synchronization that in turn is regulated by SOV. Studies demonstrating the variation in spike distribution are often constrained to cortical structures. Thalamus, a subcortical node interconnected to diverse cortical network including mesial temporal lobe, is implicated in regulation of SOV and in genesis of focal seizures. However to date, no study has explored the distribution of spike within the thalamo-cortical network in human focal epilepsy. We hypothesize, that the prevalence of spike within the SOZ and thalamus will vary with SOV and the spike count in thalamus will be higher during sleep than in wakefulness.
METHODS: Five adults with suspected temporal lobe epilepsy underwent stereoEEG (SEEG) investigation. Anterior thalamic nucleus (TH) ipsilateral to the SOZ was sampled with SEEG. The study was approved by IRB and written consent was obtained before surgery. Simultaneous scalp EEG was recorded that guided identification of NREM sleep (S) and wakefulness (A). Epileptogenic index was performed to identify SOZ. Spikes were analyzed during S and A from three channels :a) one within the SOZ; b) second from Th; and c) third outside the SOZ (control - C). Automated spike detection (P- operator) was validated by comparing the algorithm output to visual identification in 30 mins data per subject. For the spike count between SOV independent T-tests were performed to assess the bivariate relationships. Analysis of variance Welch ANOVA was used to analyze the differences in SOV as a function of three different independent samples (Channels). All statistical analyses were performed using IBM SPSS.
METHODS: A 27-year-old, right handed male with 8-year history of intractable simple (SPS),complex partial seizures (CPS) and MRI brain positive for right hippocampal sclerosis underwent standard right (non-dominant) anterior temporal lobectomy. He was seizure-free for two years, but subsequently there was resurgence of aura followed by frequent complex partial seizures. He then underwent stereo EEG investigation with ipsilateral implant targeting hippocampal remnant, lateral and basal temporal, anterior and posterior insular and posterior orbitofrontal regions. A multi-contact depth electrode with entry at the superior temporal gyrus was advanced medially to sample thalamus while the lateral contacts sampled lateral temporal neocortex (Fig 1). Seizures were identified using conventional visual analysis, HFO and ictal baseline shift. Matlab was used to analyze power spectrum, cross coherence, phase amplitude coupling and Directed transfer function analysis for substantiating functional connectivity between the seizure onset zone(s) and thalamus. Approval of the institutional review board was obtained for post-hoc analysis and publication.
RESULTS: Six seizures (2 SPS, 2 CPS and 2 secondarily generalized) with multi-focal origin were recorded during seven day SEEG monitoring and were selected for analysis. Visual analysis confirmed involvement of thalamus in CPS and sGTC seizures. Spectral analysis confirmed cortico-thalamic involvement between 100-400 Hz and the earliest involvement was within 10 seconds of seizure onset. Thalamic signatures at seizure onset differed from offset.CONCLUSIONS:In our preliminary analysis from a single patient, we can confirm that thalamus is involved in CPS and sGTC seizures. Further analysis is required to confirm the earliest time thalamus is involved with seizure onset and the directionality of cortico-thalamic interaction.
Figure 1A: An example of focal seizure with impaired awareness localized to right temporal pole, amygdala, anterior and posterior hippocampus (subject 3). Thalamogram highlighted in red. * represents the onset of oro-manual automatism. EEG visualized with input filter 1-100 Hz, Time base 15mm/sec, sensitivity 30 μV/mm.a=Amygdala, b-c=Anterior and Posterior Hippocampus, d= Temporal Pole, e-f=Anterior and Posterior Orbitofrontal, g-i=Anterior, Mid, Posterior Cingulate, j=Thalamoinsular. M represent mesial contacts while L for lateral contacts B-Receiver operator curves (ROC) for seizure detection using line length, Laplacian, and Teager energy within the anterior thalamic nuclei (left) and seizure onset zone (right). Areas under the ROC are presented. Note that the x- and y-axes have been adjusted to optimize presentation. CStereotactic placement of depth electrodes to sample right and left anterior thalamus. Points are displayed on the Talairach atlas in the axial slice.
Systems Science and Informatics Unit, Indian Statistical Institute, Kolkata, India
Department of Clinical Neurosciences, NIMHANS, Bangalore 560029, India
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA
Ten (77%) of 13 patients in the ANT group and 10 (91%) of 11 patients in the MED group had electrodes accurately placed in the thalamic nuclei. None of the patients had a thalamic hemorrhage. However, trace asymptomatic hemorrhages at the cortical-level entry site were noted in 20.8% of patients, who did not require additional surgical intervention. SEEG data from all the patients were interpretable and analyzable. The trajectories for the ANT implant differed slightly from those of the MED group at the entry point—i.e., the precentral gyrus in the former and the postcentral gyrus in the latter.
Using judiciously planned robot-assisted SEEG, the authors demonstrate the safety of electrophysiological sampling from various thalamic nuclei for research recordings, presenting a technique that avoids implanting additional depth electrodes or compromising clinical care. With these results, we propose that if patients are fully informed of the risks involved, there are potential benefits of gaining mechanistic insights to seizure genesis, which may help to develop neuromodulation therapies.
Epilepsy and Cognitive Neurophysiology Laboratory
Figure 1. (A) Postimplant CT brain coregistered with MRI to demonstrate depth electrodes (highlighted with red dots) targeted toward the midline thalamus (highlighted with yellow dots) (B) Stereo EEG recording demonstrating spontaneous seizure (FIAS) localized to left amygdala (LA), anterior and posterior hippocampus (LAH, LPH), and midline thalamus (LTh). EEG changes low amplitude fast activity (LAFA). Included below is the time-frequency decomposition (1-100 Hz) of ictal thalamogram. Note the increase in power above 15 Hz following ictal recruitment. (C) Stereo EEG recording demonstrating induced seizure (FIAS) localized to the right amygdala (RA), anterior and posterior hippocampus (RAH, RPH), and midline thalamus (RTh). Electrical stimulation was applied to RAH. D- Stereo EEG recording demonstrating evoked seizure (FAS) localized to left amygdala (LA), anterior and posterior hippocampus (LAH, LPH). Electrical stimulation was applied to left midline thalamus (LTh). FIAS, Focal impaired awareness seizure; FAS, Focal aware seizure
To investigate dynamic changes in neural activity between the anterior nucleus of the thalamus (ANT) and the seizure onset zone (SOZ) in patients with drug‐resistant temporal lobe epilepsy (TLE) based on anatomic location, seizure subtype, and state of vigilance (SOV).
Eleven patients undergoing stereoelectroencephalography for seizure localization were recruited prospectively for local field potential (LFP) recording directly from the ANT. The SOZ was identified using line length and epileptogenicity index. Changes in power spectral density (PSD) were compared between the two anatomic sites as seizures (N = 53) transitioned from interictal baseline to the posttermination stage.
At baseline, the thalamic LFPs were significantly lower and distinct from the SOZ with the presence of higher power in the fast ripple band (P < 0.001). Temporal changes in ictal power of neural activity within ANT mimic those of the SOZ, are increased significantly at seizure onset (P < 0.05), and are distinct for seizures that impaired awareness or that secondarily generalized (P < 0.05). The onset of seizure was preceded by a decrease in the mean power spectral density (PSD) in ANT and SOZ (P < 0.05). Neural activity correlated with different states of vigilance at seizure onset within the ANT but not in the SOZ (P = 0.005).
The ANT can be recruited at the onset of mesial temporal lobe seizures, and the recruitment pattern differs with seizure subtypes. Furthermore, changes in neural dynamics precede seizure onset and are widespread to involve temporo‐thalamic regions, thereby providing an opportunity to intervene early with closed‐loop DBS.
The causal role of midline thalamus in the initiation and early organization of mesial temporal lobe seizures is studied. Three patients undergoing stereoelectroencephalography were enrolled for the placement of an additional depth electrode targeting the midline thalamus. The midline thalamus was recruited in all three patients at varying points of seizure initiation (0-13 seconds) and early propagation (9-60 seconds). Stimulation of either thalamus or hippocampus induced similar habitual seizures. Seizure-induced in the hippocampus rapidly recruited the thalamus. Evoked potentials demonstrated stronger connectivity from the hippocampus to the thalamus than in the opposite direction. The midline thalamus can be within the seizure initiation and symptomatogenic circuits.
CONCLUSIONS:In temporal lobe epilepsy, the thalamus can be recruited early in the seizure onset network, and temporal trends in recruitment relate to seizure subtypes and duration of epilepsy.
FUNDING:This study was funded by the NSF EPSCoR OIA 1632891.
We define an EEG marker that delineates stimulation-specific nodal engagement. We proved that nodes that were engaged with the thalamus during stimulation were more likely to show a short term decrease in post-stimulation excitability.
Patient-specific engagement patterns during stimulation can be mapped with SEEG that can be used to optimize stimulation parameters.
RATIONALE: Thalamus, with its reciprocal connectivity to the cortex, plays a critical role in the generation and behavioral expression of focal seizures. Thalamic subnuclei have distinct connectivity patterns with the cortex and determine variable functional significance. A recent study has demonstrated ventral posteromedial nuclei (VPM) interrupted information flow causing altered consciousness, while anterior thalamus (ATN) participates in the propagation of temporal lobe seizures. Limited clinical studies have demonstrated temporal lobe seizures recruit thalamus, but an in-depth investigation of the temporal trends and predictors of thalamic recruitment is lacking. Based on the rich connectivity of ATN with mesial temporal and perisylvian structures, we hypothesize that ATN will be recruited early at the onset of temporal lobe seizures. Under the supervision of IRB, during stereo-EEG (sEEG) exploration in suspected temporal lobe epilepsy, we sampled electrical activity from ventral lateral (VL) or AT nucleus.
METHODS: From 14 patient who had a thalamic sampling (N=5 ATN, 9 VL), multiple seizures (N=2-10/subject) were analyzed to determine -a) if thalamus (TH) is recruited early at seizure onset, and b) predictors of early recruitment. Epileptogenic index (EI) (Bartolomei 2008, Colombet 2015), a quantitative measure of the likelihood of regions involved in seizure onset was estimated with EI>0.25 (Roehri 2018) used to identify seizure onset channels (SOC) and if TH is within the seizure onset network. Line length (Esteller 2001)-an efficient method of automated seizure detection was calculated in 0.5 s windows, with 50% overlap. Latency (time difference between the beginning of the seizure on SOC and TH, and between clinical onset and TH involvement) and duration of TH involvement during a seizure were calculated (Figure 1). The results were grouped by the types of the seizure classification and the thalamic area (ATN, VL). Clinical features including duration of epilepsy, baseline seizure frequency, states of vigilance preceding seizure for every subject were collected. Logistic regression was used to assess the predictors of the thalamic involvement.
RESULTS: 69 focal seizures with semiology- 11 electrographic (E), 15 with awareness (FSA), 34 with awareness impaired (FSIA), 9 with bilateral tonic-clonic (TC) were analyzed. In the ATN cohort, 83.87% (26/31) of analyzed seizures had thalamus involved in seizure onset, while in VL this was 71.05% (27/38), with no statistically significant difference between the two cohorts (p=0.21). Overall average (SD) thalamic latency: 10.6s (24.3s); VL: 13.4s (29.6s), ATN: 7.8s (17.4s) and with respect to clinical onset in overall -13.1s, (24.2s); VL: -7.6s (27.9s), ANT: -18.8s (18.6). Seizures sustained in the thalamus over 66% of the total duration, and it was maximum in TC. Significant predictors for thalamic involvement are the number of TC seizures/month and the duration of epilepsy (p=0.001 and p=0.008 respectively).